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Table 1 Factor Xa Inhibitors (TAP, Antistasin) in Experimental Models of Thrombosis
Rat and rabbit models of venous thrombosis [25]
Canine model of high shear, coronary arterial thrombosis [6,26]
Canine model of femoral arterial thrombosis [27,28]
Rhesus monkey model of acute disseminated intravascular coagulation [29,30]
Baboon model of platelet dependent arterial thrombosis [9,31,32]
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In an alternate approach, it has been shown that a covalently blocked, activesite-modified Factor Xa
(DEGR-Xa) [16] as well as a catalytically impaired recombinant form [17] can be effective
anticoagulants in models of deep-vein thrombosis [18] and in canine arterial thrombosis models [8]. In
these examples, the active-site-inactivated Factor Xa competes with the active form for incorporation
into the active prothrombinase complex since the binding of Factor Xa to Factor Va in this complex is
independent of the active site [20]. These studies with Factor Xa inhibitors suggest that inhibiting earlier
in the coagulation cascade, as well as inhibiting the production of thrombin by inactivating Factor Xa in
the prothrombinase complex, may have certain therapeutic advantages.
IV. Factor Xa—Structure and Function
Factor Xa is a 59 kilodalton protein synthesized in the liver and secreted into the blood as an inactive
zymogen (Figure 2) [21]. Prior to secretion the singlechain molecule undergoes co- and posttranslational
modifications including removal of a signal sequence [22–24], gamma carboxylation of
several glutamic acids (Gla) in the N-terminus [33], beta hydroxylation of Asp 63 [34], N-glycosylation at
two sites [35], and cleavage at two sites, Arg 139 and Arg 142, to give a two-chain molecule [36]. The
mature form of Factor X consists of a light chain (139 amino acids) and a heavy chain (303 amino acids)
held together by a single disulfide (Figure 2). The Gla residues are responsible for calcium and
phospholipid binding and the second EGF domain is thought to mediate binding to Factor VIIIa and
Factor Va [37,38]. The heavy chain contains the catalytic domain with the prototypic serine protease
active site triad, His 226, Asp 279, and Ser 376. During coagulation, Factor X is converted to the active
protease, Factor Xa, by a complex of Factor VIIa/tissue factor or a complex of Factor IXa/Factor,
VIIIa/phospholipid, and calcium, both of which cleave a specific Arg-Ile bond to release an activation
peptide (Figure 2) [39]. Similar to the activation of chymotrypsin, trypsin, and thrombin, the newly
formed N-terminal Ile folds into the interior of the protein to form an ion pair at the active site with
Asp] 375 [39,40]. In the presence of calcium ions the newly formed Factor Xa associates with Factor Va
on a phospholipid membrane surface to form the
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